Membrane hyperpolarization is a mechanism of endothelium-dependent cerebral vasodilation

1990 ◽  
Vol 259 (3) ◽  
pp. H668-H673 ◽  
Author(s):  
J. E. Brayden
Keyword(s):  
Nitric Oxide ◽  
Methylene Blue ◽  
Potassium Channel ◽  
Cerebral Arteries ◽  
Channel Blockers ◽  
Membrane Hyperpolarization ◽  
Middle Cerebral Arteries ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Cerebral Vasodilation

Acetylcholine (ACh)-induced hyperpolarization of cerebral arteries requires a functional endothelium. The hyperpolarization is reversed by potassium-channel blockers. The goal of this study was to determine whether the hyperpolarization is causally related to endothelium-dependent dilation of isolated cerebral arteries. ACh hyperpolarized rabbit middle cerebral arteries by up to 19 mV. The hyperpolarizations were sustained and did not occur in arteries without endothelial cells or in the presence of potassium-channel inhibitors (3 x 10(-6) M glibenclamide or 5 x 10(-5) M BaCl2). ACh-induced dilator responses were inhibited but not abolished by glibenclamide or BaCl2. Methylene blue also inhibited the dilator responses, and a combination of glibenclamide or BaCl2 and methylene blue greatly diminished the dilation. Nitric oxide relaxed but did not hyperpolarize the vascular smooth muscle cells, and BaCl2 had no effect on the nitric oxide-induced relaxations. These data indicate that the overall cerebral arterial dilator response to ACh is determined by the combined effects of membrane hyperpolarization, which closes voltage-dependent calcium channels, and the actions of a second endothelial factor, probably endothelium-derived relaxing factor.

Abstract 357: Cerebral Arterial Endothelial Dysfunction in the Post-Cardiac Arrest Period

Circulation ◽  
2019 ◽  
Vol 140 (Suppl_2) ◽  
Author(s):  
Frederik B Hansen ◽  
Goncalo Esteves ◽  
Niels Secher ◽  
Bo Lofgren ◽  
Ulf Simonsen ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Endothelial Dysfunction ◽  
Cerebral Arteries ◽  
Channel Blockers ◽  
Sprague Dawley ◽  
No Donor ◽  
Sprague Dawley Rats ◽  
Middle Cerebral Arteries ◽  
Cerebral Vasodilation ◽  
Synthase Inhibitor

Introduction: Cardiac arrest (CA) has a poor prognosis due to brain injury that progresses over time. Endothelial dysfunction may play an important role in the impairment of the cerebral circulation after CA. Aims: To investigate 1) whether endothelial dysfunction is present in cerebral arteries, and 2) if the altered endothelial function is caused by increased activity of calcium-activated potassium (K ca ) channels. Methods: Male Sprague-Dawley rats (403g±24g) were anaesthetized, intubated and ventilated. Four groups were examined; two CA groups observed for either 2 hours (2h-CA, n=10) or 4 hours (4h-CA, n=10) and two corresponding sham groups (2h-sham, n=10; 4h-sham, n=10). Following 7 minutes of asphyxial CA, the rats were resuscitated using adrenaline, ventilation, and chest compressions. Middle cerebral arteries were isolated and examined in wire-myographs. Results: Cerebral vasodilation was significantly enhanced in response to bradykinin in arteries from 4h-CA rats when compared to 4h-sham rats (4h-sham: E max 58% (5.57 of 9.69) ± 6% vs 4h-CA: E max 84% (6.16 of 7.32) ± 4%, p=0.007). Likewise, vasodilation induced by NS309 (K Ca -channel activator) was increased in CA rats when compared to sham rats. In the presence of L-NAME (NO synthase inhibitor), bradykinin induced vasodilation was significantly augmented in 4h-CA rats when compared to 4h-sham rats, whereas SNP (NO donor) induced vasodilation was similar between groups. In the presence of L-NAME and K Ca -channel blockers (UCL1684 and ICA-17043), bradykinin induced vasodilation was abolished in cerebral arteries in all four groups. Conclusion: Our findings demonstrate an enhanced endothelial-dependent vasodilation in cerebral arteries in the post-cardiac arrest period. The increased vasodilatory response may be explained by increased endothelial K Ca -channel activity and bioavailability of NO, and may contribute to dysregulation of cerebral blood flow after CA.

scholarly journals Dihydropyridine-Insensitive Calcium Currents Contribute to Function of Small Cerebral Arteries

2010 ◽  
Vol 30 (6) ◽  
pp. 1226-1239 ◽  
Author(s):  
Ivana Y Kuo ◽  
Anthie Ellis ◽  
Victoria AL Seymour ◽  
Shaun L Sandow ◽  
Caryl E Hill
Keyword(s):  
Cerebral Arteries ◽  
Calcium Currents ◽  
Adult Rat ◽  
Cerebrovascular Function ◽  
Middle Cerebral Arteries ◽  
Voltage Dependent ◽  
Basilar Arteries ◽  
Voltage Dependent Calcium Channels ◽  
Patch Clamp Electrophysiology

Although dihydropyridines are widely used for the treatment of vasospasm, their effectiveness is questionable, suggesting that other voltage-dependent calcium channels (VDCCs) contribute to control of cerebrovascular tone. This study therefore investigated the role of dihydropyridine-insensitive VDCCs in cerebrovascular function. Using quantitative PCR and immunohistochemistry, we found mRNA and protein for L-type (CaV1.2) and T-type (CaV3.1 and CaV3.2) channels in adult rat basilar and middle cerebral arteries and their branches. Immunoelectron microscopy revealed both L- and T-type channels in smooth muscle cell (SMC) membranes. Using patch clamp electrophysiology, we found that a high-voltage-activated calcium current, showing T-type channel kinetics and insensitivity to nifedipine and nimodipine, comprised ∼20% of current in SMCs of the main arteries and ∼45% of current in SMCs from branches. Both components were abolished by the T-type antagonists mibefradil, NNC 55-0396, and efonidipine. Although nifedipine completely blocked vasoconstriction in pressurized basilar arteries, a nifedipine-insensitive constriction was found in branches and this increased in magnitude as vessel size decreased. We conclude that a heterogeneous population of VDCCs contributes to cerebrovascular function, with dihydropyridine-insensitive channels having a larger role in smaller vessels. Sensitivity of these currents to nonselective T-type channel antagonists suggests that these drugs may provide a more effective treatment for therapy-refractory cerebrovascular constriction.

Modulation of cerebral arterial tone by endothelium-derived relaxing factor

1993 ◽  
Vol 264 (4) ◽  
pp. H1245-H1250 ◽  
Author(s):  
J. E. Brian ◽  
R. H. Kennedy
Keyword(s):  
Nitric Oxide ◽  
Muscle Tone ◽  
Cerebral Arteries ◽  
Maximum Tension ◽  
Relaxing Factor ◽  
Middle Cerebral Arteries ◽  
Endothelium Derived Relaxing Factor ◽  
Vascular Smooth Muscle Tone ◽  
Dose Dependent ◽  
Arterial Tone

This study was designed to further elucidate the role of the endothelium in regulation of cerebral vascular smooth muscle tone. Dose-dependent vasoconstrictive effects of serotonin (5-HT) were examined in endothelium-intact and endothelium-denuded ring segments prepared from canine basilar and middle cerebral arteries. Some preparations were pretreated with 10(-5) M N omega-nitro-L-arginine (L-NNA), an agent that inhibits the production of L-arginine-derived nitric oxide, one of the compounds proposed to be endothelium-derived relaxing factor. L-NNA alone elicited marked dose-dependent increases in tension in endothelium-intact preparations; a significantly smaller response was seen in endothelium-denuded preparations. The effects of L-NNA on endothelium-intact preparations were partially reversed by washing and treatment with L-arginine. The maximum tension induced by 5-HT was approximately doubled by removal of the endothelium as well as by L-NNA treatment of endothelium-intact preparations; a slight increase in maximum tension occurred in endothelium-denuded preparations treated with L-NNA. The concentration of 5-HT producing half-maximal contraction (ED50) was not affected by L-NNA. These data suggest that L-arginine-derived nitric oxide modulates canine cerebral arterial tone in both the resting state and during contraction with 5-HT.

scholarly journals Engineering selectivity into RGK GTPase inhibition of voltage-dependent calcium channels

2018 ◽  
Vol 115 (47) ◽  
pp. 12051-12056 ◽  
Author(s):  
Akil A. Puckerin ◽  
Donald D. Chang ◽  
Zunaira Shuja ◽  
Papiya Choudhury ◽  
Joachim Scholz ◽  
...  
Keyword(s):  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Hek293 Cells ◽  
Channel Blockers ◽  
Wild Type ◽  
Voltage Dependent ◽  
Somatosensory Neurons ◽  
Potential Applications ◽  
Voltage Dependent Calcium Channels ◽  
Potential Therapeutics

Genetically encoded inhibitors for voltage-dependent Ca2+ (CaV) channels (GECCIs) are useful research tools and potential therapeutics. Rad/Rem/Rem2/Gem (RGK) proteins are Ras-like G proteins that potently inhibit high voltage-activated (HVA) Ca2+ (CaV1/CaV2 family) channels, but their nonselectivity limits their potential applications. We hypothesized that nonselectivity of RGK inhibition derives from their binding to auxiliary CaVβ-subunits. To investigate latent CaVβ-independent components of inhibition, we coexpressed each RGK individually with CaV1 (CaV1.2/CaV1.3) or CaV2 (CaV2.1/CaV2.2) channels reconstituted in HEK293 cells with either wild-type (WT) β2a or a mutant version (β2a,TM) that does not bind RGKs. All four RGKs strongly inhibited CaV1/CaV2 channels reconstituted with WT β2a. By contrast, when channels were reconstituted with β2a,TM, Rem inhibited only CaV1.2, Rad selectively inhibited CaV1.2 and CaV2.2, while Gem and Rem2 were ineffective. We generated mutant RGKs (Rem[R200A/L227A] and Rad[R208A/L235A]) unable to bind WT CaVβ, as confirmed by fluorescence resonance energy transfer. Rem[R200A/L227A] selectively blocked reconstituted CaV1.2 while Rad[R208A/L235A] inhibited CaV1.2/CaV2.2 but not CaV1.3/CaV2.1. Rem[R200A/L227A] and Rad[R208A/L235A] both suppressed endogenous CaV1.2 channels in ventricular cardiomyocytes and selectively blocked 25 and 62%, respectively, of HVA currents in somatosensory neurons of the dorsal root ganglion, corresponding to their distinctive selectivity for CaV1.2 and CaV1.2/CaV2.2 channels. Thus, we have exploited latent β-binding–independent Rem and Rad inhibition of specific CaV1/CaV2 channels to develop selective GECCIs with properties unmatched by current small-molecule CaV channel blockers.

scholarly journals Action Potentials in Rhodnius Oocytes: Repolarization is Sensitive to Potassium Channel Blockers

1986 ◽  
Vol 126 (1) ◽  
pp. 119-132
Author(s):  
M. J. O'DONNELL
Keyword(s):  
Potassium Channel ◽  
Action Potentials ◽  
Potassium Conductance ◽  
Channel Blockers ◽  
Calcium Dependent ◽  
Outward Rectification ◽  
Current Voltage ◽  
Potassium Channel Blockers ◽  
Potassium Conductances ◽  
Voltage Dependent

Depolarization of Rhodnius oocytes evokes action potentials (APs) whose rising phase is calcium-dependent. The ionic basis for the repolarizing (i.e. falling) phase of the AP was examined. Addition of potassium channel blockers (tetraethylammonium, tetrabutylammonium, 4-aminopyridine, atropine) to the bathing saline increased the duration and overshoot of APs. Intracellular injection of tetraethyl ammonium had similar effects. These results suggest that a voltage-dependent potassium conductance normally contributes to repolarization. Repolarization does not require a chloride influx, because substitution of impermeant anions for chloride did not increase AP duration. AP duration and overshoot actually decreased progressively when chloride levels were reduced. Current/voltage curves show inward and outward rectification, properties often associated with potassium conductances. Outward rectification was largely blocked by external tetraethylammonium. Possible functions of the rectifying properties of the oocyte membrane are discussed.

scholarly journals Time Course of Changes in Nitric Oxide Synthases Following Subarachnoid Hemorrhage in Primates

Stroke ◽  
2001 ◽  
Vol 32 (suppl_1) ◽  
pp. 359-360
Author(s):  
Robert L Macdonald ◽  
Bak Yamini ◽  
Bryce K Weir ◽  
Shigeki Ono
Keyword(s):  
Nitric Oxide ◽  
Subarachnoid Hemorrhage ◽  
Time Course ◽  
Cerebral Arteries ◽  
Inflammatory Cells ◽  
Inos Mrna ◽  
Messenger Ribonucleic Acid ◽  
Fold Reduction ◽  
Middle Cerebral Arteries ◽  
The Right

P114 Nitric oxide (NO) may be important in vasospasm following subarachnoid hemorrhage (SAH). We evaluated the time course of changes in 3 isoforms of NO synthase (NOS) after SAH in monkeys. Right SAH was created and vasospasm was assessed on angiograms obtained at baseline and after 3, 7 and 14 days. Animals were euthanized at these times (n = 4 - 6 per time) and the right and left (control) middle cerebral arteries were removed. Levels of nNOS, eNOS and iNOS messenger ribonucleic acid (mRNA) and protein were measured by reverse transcriptase polymerase chain reaction and Western blotting. Angiography showed a 45 ± 13% (mean ± s.d., p < 0.05) decrease in middle cerebral artery diameter 3 days, a 41 ± 23% (p< 0.05) decrease 7 days and an insignificant 6 ± 14% decrease 14 days after SAH. The RNA for eNOS was significantly reduced (1.7 ± 0.5-fold) 7 days after SAH. There was a significant, 1.7 ± 0.2-fold reduction in eNOS protein on days 3 and 7 after SAH that returned to normal by day 14. There were no significant changes in nNOS mRNA or protein at any time after SAH. There were no significant changes in iNOS mRNA whereas iNOS protein increased on days 3 and 7 (7 ± 9 and 2.7 ± 2.8-fold, respectively, p > 0.05) and significantly decreased (2.7 ± 1.1-fold, p < 0.05) on day 14. Immunohistochemistry localized eNOS to endothelium, nNOS to brain and perivascular adventitia of the middle cerebral arteries and iNOS to inflammatory cells in the subarachnoid space. These results show a correlation between decreased eNOS and increased iNOS during vasospasm, suggesting a complex role for changes in NO in vasospasm.

Nitric oxide-synthesizing perivascular nerves in the rat middle cerebral artery

1997 ◽  
Vol 273 (2) ◽  
pp. R661-R668 ◽  
Author(s):  
C. S. Ignacio ◽  
P. E. Curling ◽  
W. F. Childres ◽  
R. M. Bryan
Keyword(s):  
Nitric Oxide ◽  
Methyl Ester ◽  
Cerebral Arteries ◽  
Middle Cerebral Arteries ◽  
Nerve Bundles ◽  
Perivascular Nerves ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Ethmoidal Foramen ◽  
Active Precursor

Although perivascular nerves containing nitric oxide synthase (NOS) have been anatomically described for rat cerebral arteries, a dilator function for these nerves has eluded investigators when using isolated vessels. Rat middle cerebral arteries (MCAs) were isolated, pressurized, and electrically stimulated. The resting diameter of the MCAs after pressurization was 233 +/- 4 microns (n = 17) in one study. The MCAs showed a frequency-dependent dilation when stimulated. Maximum dilation (25-30% increase in diameter) occurred at a frequency of 8-16 Hz. Removal of endothelium or glibenclamide (10(-5) M), a blocker of ATP-sensitive potassium channels, had no effect on the dilations. The dilations were completely blocked with NG-nitro-L-arginine methyl ester (L-NAME) (10(-5) M), a general NOS inhibitor, and cold storage (24 h). The inhibition by L-NAME could be reversed by the addition of 10(-8) M L-arginine, the active precursor of NOS. Furthermore, 7-nitroindazole (10(-4) M), an inhibitor specific for the neuronal isoform of NOS, reduced the dilations by 43% (P < 0.05). Transections of nerve bundles originating from the sphenopalatine ganglia at the ethmoidal foramen blocked the dilations produced by electrical stimulations. We conclude that rat cerebral arteries have functionally intact perivascular nerves that dilate by releasing nitric oxide.

Endothelium modulates anion channel-dependent aortic contractions to iodide

2000 ◽  
Vol 278 (5) ◽  
pp. H1527-H1536 ◽  
Author(s):  
Fred S. Lamb ◽  
Thomas J. Barna
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Membrane Potential ◽  
Anion Channel ◽  
Anion Channels ◽  
Anion Substitution ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Channel Dependent ◽  
Cytochrome P 450

Anion currents contribute to vascular smooth muscle (VSM) membrane potential. The substitution of extracellular chloride (Cl) with iodide (I) or bromide (Br) initially inhibited and then potentiated isometric contractile responses of rat aortic rings to norepinephrine. Anion substitution alone produced a small relaxation, which occurred despite a lack of active tone and minimal subsequent contraction of endothelium-intact rings (4.2 ± 1.2% of the response to 90 mM KCl). Endothelium-denuded rings underwent a similar initial relaxation but then contracted vigorously (I > Br). Responses to 130 mM I (93.7 ± 1.9% of 90 mM KCl) were inhibited by nifedipine (10− 6 M), niflumic acid (10− 5 M), tamoxifen (10− 5 M), DIDS (10− 4 M), and[Formula: see text]-free buffer (HEPES 10 mM) but not by bumetanide (10− 5 M). Intact rings treated with N ω-nitro-l-arginine (10− 4 M) responded weakly to I (15.5 ± 2.1% of 90 mM KCl), whereas hemoglobin (10− 5 M), indomethacin (10− 6 M), 17-octadecynoic acid (10− 5 M), and 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (10− 6 M) all failed to augment the response of intact rings to I. We hypothesize that VSM takes up I primarily via an anion exchanger. Subsequent I efflux through anion channels having a selectivity of I > Br > Cl produces depolarization. In endothelium-denuded or agonist-stimulated vessels, this current is sufficient to activate voltage-dependent calcium channels and cause contraction. Neither nitric oxide nor prostaglandins are the primary endothelial modulator of these anion channels. If they are regulated by an endothelium-dependent hyperpolarizing factor it is not a cytochrome P-450 metabolite.

scholarly journals Hemolysate Inhibits Cerebral Artery Relaxation

1988 ◽  
Vol 8 (1) ◽  
pp. 46-53 ◽  
Author(s):  
Noboru Toda
Keyword(s):  
Methylene Blue ◽  
Angiotensin Ii ◽  
Substance P ◽  
Cerebral Arteries ◽  
Vascular Wall ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Middle Cerebral Arteries ◽  
Relaxant Response ◽  
Stimulation Of

In helical strips of dog middle cerebral arteries partially contracted with prostaglandin (PG) F2α, relaxations induced by angiotensin-II, possibly mediated by PGI2, and those induced by PGH2 were reversed to a contraction or markedly reduced by treatment with hemolysate, which, however, attenuated the PGI2-induced relaxation only slightly. The relaxant response of human middle cerebral arterial strips to PGH2 was also suppressed by hemolysate. Dog and monkey middle cerebral arteries responded to transmural electrical stimulation and nicotine with transient relaxations, which were quite susceptible to tetrodotoxin and hexamethonium, respectively; the relaxations were abolished almost completely by hemolysate and methylene blue. On the other hand, the relaxant response of dog cerebral arteries to a low concentration of K+ was not influenced by hemolysate or by methylene blue, but was reversed to a contraction by treatment with ouabain. Relaxations induced by substance-P and nitroglycerin were markedly inhibited by hemolysate; removal of endothelium abolished the relaxation by substance-P, but did not influence the nitroglycerin-induced relaxation. Hemolysate may interfere with the biosynthesis of PGI2 in the vascular wall, thereby reversing the relaxation induced by angiotensin-II and PGH2 to a contraction. Relaxations induced by electrical and chemical stimulation of vasodilator nerves innervating cerebral arteries appear to be elicited by a mechanism dependent on cellular cyclic guanosine monophosphate (GMP), like that underlying the substance-P-induced and nitroglycerin-induced relaxation. These actions of hemolysate may be involved in the genesis of cerebral vasospasm after subarachnoid hemorrhage.

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